USPTO Patents Application 09926218

(§)•

J

Europaisches Patentamt
European Patent Office
Office europeen des brevets

© Publication number:

0 366 990

A2

®

EUROPEAN PATENT APPLICATION

© Application number: 89118956.5
© Date of filing: 12.10.89

© lnt.Ci>A61K 31/41 , A61K 47/24 ,
A61K 9/08

© Priority: 29.10.88 DE 3838892

© Applicant: A. Nattermann & Cie. GmbH

Nattermannallee 1

© Date of publication of application:

D-500O Koln 30(DE)

09.05.90 Bulletin 90/19

@ Inventor Hager, Jorg

© Designated Contracting States:

Hermann-Josef-Schmitt-Strasse 48

AT BE CH DE ES FR GB GR IT U LU NL SE

D-5000 Koln 30(DE)

Inventor: HUther, Andrea Michaela

Brauweiler Weg 133

D-5000 Koln 41 (DE)

Inventor: Roding, Joachim

Welssenburger Strasse 13

D-5000 Koln 1(DE)

© Representative: PatentanwaltsbUro Cohausz &

Florack

Schumannstrasse 97

D-4000 DUsseldorf 1(DE)

© Stabile parenteral solution of 2-phenyl-1.2-benzisoselenazol-3(2H)-one and process for producing
the same.

© The present invention is related to new parenteral preparations of 2-phenyM .2-benzisosetenazol- 3(2H)-one
(Ebselen) comprising additionally one orseveral phospholipids and, possibly, one or several auxiliary agents. The
invention is further related to a process for producing such solutions and their use in the preparation of drug
preparations ob Ebselen.

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EP 0 366 990 A2

Stabile parenteral solution of 2-phenyM.2-benzisoselenazol-3(H)-one and process for producing the

same

The present invention is related to new solutions which may be parenterally administer and which
comprise 2-phenyi 1 .2-benzisoselenazol-3{2H)-one (Ebselen) in combination with one or several
phospholipids in a weight proportion of from 1:2500 to 1:15 and, possibly, one or several auxiliary agents.
The invention is further related to the production of such solutions as well as their use in the production of
s drug preparations comprising 2-phenyl-1.2-benzisoselenazol-3(2H)-one (Ebselen) and one . or several
phospholipids.

Ebselen is a known product (DE-PS 3027073). It may be produced by the process of R. Weber and M.
Renson, Bulletin de la Soc. Chim. de France 1976 (7/8), pgs. 1124-1126, by subjecting 2-methylseleno-N-
phenyl-benzamide to reaction with phosphorous pentachloride and subsequently hydrolysing the obtained

w product. Preparations comprising Ebselen may be used in the treatment of numerous diseases such as the
prophylaxis and therapy of infection diseases, the therapy of malignent tumors (DE-OS 3638124). for
stimulating the immuno system or for the treatment of selen deficiency diseases. Further attention is drawn
to the application of the anti-artheriosclerotic and anti-inflammatory properties of Ebselen and their
application in the therapy of rheumatic diseases (DE-OS 3027073). Ebselen ist furthermore an important

is agent useful in the therapy of deficiencies caused by oxydative stress (DE-OS 3616920) such is lever
deficiencies, cardiac infarction, psoriasis and diseases caused by radiation. There is known also a drug
preparation for the topical use of Ebselen (DE-OS 3620674), which may be used in the external treatment of
inflammatory and allergic skin diseases such as psoriasis.

The broad spectrum of properties is in contrast to a very low solubility of Ebselen in water. Due thereto

20 the use of Ebselen in the form of parenteral solutions is prevented. Preparations comprising organic
solvents containing Ebselen dissolved therein do not provide satisfactory results because diluting such
solutions with water for injections or with physiological saline solutions cause precipitation of crystals of
Ebselen.

It has now been found that surprisingly stabile aqueous solutions of 2-phenyM .2-benzisoselenazol-3-
25 (2H)-one (Ebselen) having a physiological pH may be produced by combining Ebselen with one or several

natural or synthetic phospholipids and this in a weight proportion of Ebselen to phospholipid amounting to a

ratio ranging from 1:2500 to 1:15. Possibly, further auxiliary agents may be added.

In this way, new aqueous solutions of Ebselen in combination with one or several phospholipids are

formed. Such solutions are very suitable for parenteral administration (for instance for intramuscular or
30 intravenous administration) and such solutions show a long existing effectiveness.

For producing such solutions, the components thereof are added to each other and stirred to produce

homogenous solutions in usual manners, for instance by aid of high pressure homogenators. In some

instances it is possible to obtain the solutions by simple stirring. Another possibility to produce the solutions

is treatment with ultrasonics or by using the so called "French Press".
35 Products to produce isotonic solutions may be added before or after the preparation of the homogenous

solutions. Such products are sodium chloride, glucose or the like. It may be advantageous to add a base,

for instance soda lye or a buffer agent in order to produce a pH close to the physiological pH. The solutions

thus prepared may be sterilized in usual manners and filled into ampoules as usual.

In view of the sensitivity of the phospholipids against light and oxygen, it may be preferable to work
40 with the exclusion of oxygen and in a protective atmosphere, and with the exclusion of light.

Both natural and synthetic phospholipids may be used. Natural phospholipids (of plant or animal origin)

are in particular phosphatidyl choline, phosphatidyl ethanolamine. phosphatidyl inosit, phosphatidyl glycol,

cardiolipine or plasmalogenes, which products may be recovered from soybeans or from eggs. Further

useful are mixtures of several such phospholipids such as the trade products
45 Phospholipon 100 (95% natural phosphatidylcholine from soybeans)

Phospholipon (R) 100 H (98% fully hydrogenated phosphatidylcholine from soybeans) Phospholipon (R> 80

(phospholipids from soybeans comprising 76% of phosphatidylcholine and 12% of

phosphatidylethanolamine).

Synthetic phosphatides are for instance:
so dihexadecanoylphosphatidylcholine,

ditetradecanoylphosphatidylcholine,

dioleylphosphatidylcholine,

dilinolylphosphatidylcholine,

in particular

2

EP 0 366 990 A2

dipalmitoy (phosphatidylcholine and
dipalmitoylphosphatidylglycerol.

Auxiliary agents are for instance cholesterol, derivatives of bile acids and salts thereof, benzylalcohol,
neutral oils (Miglyol 812) and glycerol.
5 The production of the preparations according to the present invention is further illustrated in the
following examples.

Example 1

Ebselen

0.110 g

DPPC (dipalmitoyiphosphatidylcholine)

13.330 g

DPPG (dipaimitoylphosphatidylglycerol)

1.330 g

cholesterol

6.450 g

buffering agent to pH4

up to 1000 ml

Ebselen. DPPC, DPPG and cholesterol are dissolved in a mixture of 1 part of methanol and 1 part of
chloroform. The solvent is removed and the resulting film is hydrated with buffer under an inert gas. Glas
balls are added and liposomes are formed with stirring. They are filtered in usual manner under sterile
conditions and filled into ampoules.

Example 2

Ebselen

0.150 g

DPPC

18.180 g

DPPG

1.818 g

cholesterol

8.790 g

water for injections

up to 1000 ml

30

The products are mixed and further processed as described in example 1 .

Example 3

Ebselen

0.250 g

DPPC

30.300 g

DPPG

3.030 g

cholesterol

14.650 g

buffering agent

up to 1000 ml

The products are mixed and further processed as described in example 1 .

Example 4

Ebselen

0.330 g

DPPC

39.970 g

DPPG

3.997 g

cholesterol

19.338 g

buffering agent

up to 1000 ml

55 The products are mixed and further processed as described in example 1 .

3

EP 0 366 990 A2

Example 5

Ebselen

0.400 g

DPPC

48.480 g

DPPG

4.848 g

cholesterol

23.440 g

buffering agent

up to 1000 ml

The products are mixed and further processed as described in in example 1.

Example 6

Ebselen

0.430 g

DPPC

50.170 g

DPPG

5.017 g

cholesterol

24.112 g

buffering agent

up to 1000 ml

20

The products are mixed and further processed as described in in example 1 .

Example 7

Ebselen

0.100 g

Phospholipon (R1 100

45.215 g

sodiumdesoxycholate

17.621 g

benzylalcohol

1 5.700 g

water for injections

up to 1000 ml

Ebselen and Phospholipon 100 are dissolved in ethanol. After removal of the solvent under vacuum, the
resulting mixture is stirred into a solution of sodiumdesoxycholate. After the addition of benzylalcohol and
water as described in example 1, the solution is filtered under sterile conditions and filled into ampoules.

Example 8

Ebselen

0.300 g

Phospholipon (R} 100

116.900 g

sodiumdesoxycholate

45.900 g

benzylalcohol

15.700 g

water for injections

up to 1000 ml

45

The products are mixed and further processed as described in in example 7.

Example 9

Ebselen

0.300 g

Phospholipon {R) 100

11 6.900 g

gfycocholin acid

58.200 g

NaOH

5.000 g

benzylalcohol

1 5.700 g

water for injections

up to 1000 ml

4

EP 0 366 990 A2

Example 10

Ebseien

0.300 g

Phospholipon (R> 80

116.900 g

imrocholin acid

64.370 g

NaOH

5.000 g

benzylalcohot

15.700 g

water for injections

up to 1000 ml

JO

The products are mixed and further processed as described in in example 7.

Example 1 1

Ebseien

0.450 g

Phospholipon (R) 100

110.440 g

sodium cholate

40.125 g

benzylalcohot

15.700 g

water for injections

up to 1000 ml

The products are mixed and further processed as described in in example 7.

Example 12

Ebseien

0.500 g.

Phospholipon (R> 80

108.700 g

water for injections

up to 1000 ml

Ebseien and Phospholipon (R > 100 are dispersed with stirring in water for injection purposes. The
resulting mixture is treated in the high pressure homogenator. The further subsequent filtration under sterile
conditions and filling into ampoules is executed as described in example 1.

Example 13

Ebseien

0.420 g

Phospholipon (R) 80

111.250 g

water for injections

up to 1000 ml

The products are mixed and further processed as described in in example 12.

45

Example 1 4

Ebseien

0.200 g

lecithins

20.000 g

Miglyol 812

170.000 g

glycerol

16.000 g

water for injections

up to 1000 ml

Ebseien is dissolved in Miglyol 812 and lecithine (solution I). Glycerol is added to the water for injection
purposes (solution II). Both solutions are mixed and treated in the high pressure homogenator. The resulting
emulsion is stirilised in the autoclave and Riled into ampoules as usual.

5

EP 0 366 990 A2

Example 1 5

Ebselen

0.500 g

lecithine

24.000 g

Migiyol 812

200.000 g

glycerol

32.000 g

water for injections

up to 1000 ml

The products are mixed and further processed as described in in example 14.

Example 16

Ebselen

1.000 g

lecithine

24.000 g

Migiyol 812

200.000 g

glycerol

32.000 g

water for injections

up to 1000 ml

20

The products are mixed and further processed as described in in example 14.

Example 17

Ebselen

2.000 g

lecithine

32.000 g

Migiyol 812

220.000 g

glycerol

37.000 g

water for injections

up to 1000 ml

The products are mixed and further processed as described in in example 14.
Claims

1. Stabile parenteral solutions of 2-phenyM.2-benzisoselenazol-3(2H)-one, characterized in that they
contain a water-soluble combination of 2-phenyM.2-benzisoseIenazol-3(2H)-one with one or several
phospholipids.

2. Solution according to claim 1, characterized in that the weight proportion of 2-phenyl-1.2-
benzisoselenazol-3(2H)-one and the phospholipid or phospholipids in the solution is between 1:2500 to 1:15.

3. Solution according to claim 1 or 2, characterized in that the phospholipid or the phospholipids
represent natural or synthetic phospholipids.

4. Solution according to claims 1 to 3, characterized in that it comprises as natural phospholipid the
compound soybean lecithine or egg lecithine or a highly purified fraction thereof.

5. Solution according to claims 1 to 3, charcterized in that the synthetic phospholipid is phosphatidyl
choline, phosphatidyl glycerol or a mixture thereof.

6. Process for producing drug preparations as claimed in claims 1 to 5, characterized in that 2-phenyl-
1.2-benzisoselenazol-3(2H)-one (Ebselen) is mixed with the phospholipid or a mixture of several
phospholipids and, possibly, one or several additional auxiliary agents in known manner, the mixture is
added to a physiological saline solution, the resulting physiological solution is rendered neutral, possibly by
means of additional auxiliary agents, and the resuling solution is rendered sterile.

7. The use of solutions according to any of claims 1 to 5 comprising a combination of 2-phenyl-1 .2-
benzisoselenazoi-3(2H)one (Ebselen) and one .or several phospholipids and, possibly, one or several
auxiliary agents, for the preparation of drugs.

6